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Induction and evasion of innate immunity by paramyxoviruses

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  • Full or part time
    Prof Goodbourn
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

In order to establish a productive infection viruses have to make significant efforts to evade the innate immune response. Of major significance is the ability to block the production or action of type I interferon (IFN). We are studying how paramyxoviruses (a group of viruses that includes the well-known mumps and measles viruses, and also includes major human respiratory pathogens parainfluenzaviruses 1 – 5) are detected by the host and how these viruses evade the IFN system.

Paramyxoviruses are non-segmented negative-stranded RNA viruses. Unlike some RNA viruses, the incoming paramyxovirus/viral RNA is not detected by the host; rather immune-activating pathogen-associated molecular patterns (PAMPs) are generated by transcription of the viral genome [1]. Our current data indicate that paramyxoviruses retain tight control over the production of new viral RNA, driven by a need to minimize immune activation. Our data [ref 2 and unpublished] also indicate that paramyoxviruses are able to generate PAMPs that activate both arms of the cytoplasmic RNA recognition system (the pattern recognition receptors, RIG-I and mda5). One key component of the PhD project will be to examine how viral RNA synthesis is regulated with respect to limiting the generation of these PAMPs using genetically-modified paramyxoviruses and host cells.

These negative-stranded RNA viruses have simple genomes, encoding just six genes essential for virus replication. In addition, most paramyxoviruses utilize an alternative reading frame of the RNA polymerase P gene to encode a “luxury function”, a product that is dispensable for replication in culture, but which is essential for evading innate immunity [reviewed in refs 3 and 4]. For example, the V protein of parainfluenzavirus 5 targets IFN production by inhibiting the function of both mda-5 and RIG-I, and also targets IFN signaling by instructing infected cells to destroy STAT1. Although mda-5 appears to be a common target for paramyxovirus V proteins [5, 6, 7], it is becoming clear that some V proteins may have additional targets [8, 9, 10]. The second component of this PhD project will be to characterize novel mechanism(s) by which selected antagonists target the IFN system. These experiments will form part of a broad degree of activity within this area by our laboratory.

Funding Notes

UK or EU applicants only - students will receive a stipend (at MRC rates) and fees will be paid on your behalf.
Please contact Professor Goodbourn directly for the application and reference forms at the email address given
The start date for the studentship will be 01 April 2016.

References

1. Killip, M.J., Young, D.F., Precious, B., Goodbourn, S. and Randall R.E. (2012). Activation of the IFN- promoter by paramyxoviruses in the absence of virus protein synthesis and genome replication. J. Gen. Virol. 93, 299-307.
2. Killip, M., Young, D., Gatherer, D., Ross, C., Short, J., Davison, A., Goodbourn, S., and Randall, R. J. (2013). Deep sequencing analysis of defective genomes of parainfluenza virus 5 and their role in interferon induction. J. Virol. 87, 4798-4807.
3. Randall, R. and Goodbourn, S. (2008). Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J. Gen. Virol. 89, 1-47.
4. Goodbourn, S. and Randall, R.E. (2009). The regulation of type I interferon production by paramyxoviruses. J. Interferon and Cytokine Research 29, 539-547.
5. Andrejeva, J., Childs, K.S., Young, D.F., Carlos, T.S., Stock, N., Goodbourn, S., and Randall, R.E. (2004). The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc. Natl. Acad. Sci. USA 101, 17264-17269.
6. Childs, K., Stock, N., Ross, C., Andrejeva, J., Hilton, L., Skinner, M., Randall, R.E., and Goodbourn, S. (2007). mda-5, but not RIG-I, is a common target for paramyxovirus V proteins. Virology 359, 190-200.
7. Childs, K.S., Andrejeva, J., Randall, R.E. and Goodbourn, S. (2009). Mechanism of mda-5 inhibition by paramyxovirus V proteins. J. Virol. 83, 1465-1473.
8. Childs, K., Randall, R. and Goodbourn, S. (2012). Paramyxovirus V proteins interact with LGP2 to inhibit RIG-I-dependent interferon induction. J. Virol. 86, 3411-3421.
9. Childs, K., Randall, R. and Goodbourn, S. (2013). LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA. PLoS ONE 8(5): e64202. doi:10.1371/journal.pone.0064202
10. Pichlmair, A., Kandasamy, K., Alvisi, G., Mulhern, O., Sacco, R., Habjan, M., Binder, M., Stefanovic, A., Eberle, C.A., Goncalves, A., Bürckstümmer, T., Müller, A.C., Fauster, A., Holze, C., Lindsten, K., Goodbourn, S., Kochs, G., Weber, F., Bartenschlager, R., Bowie, A.G., Bennett, K.L., Colinge, J., Superti-Furga, G. (2012). Viral immune modulators perturb the human molecular network by common and unique strategies. Nature, 487, 486-490.

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